Over 10 million Americans carry at least one major implanted medical device in their body. Among these implants, bone fracture and damage cases constitute a large proportion, and result in more than 1.3 million bone-repair procedures per year in the USA. In general, bone tissue has the capability of postnatal self-construction. However, in severe pathological situations such as complicated fractures, trauma, bone tumors, congenital defects or spinal fusion, the damaged bone will not form or regenerate spontaneously. To repair the damaged bone, autografts, long-considered the gold standard in bone grafting, have problems of resource limitation and morbidity associated with graft harvest, while the allogenic bones from tissue banks have the disadvantages of immune response due to genetic differences and the risk of inducing transmissible diseases. As a result, various synthetic materials have been developed for bone repair applications.
Since the discovery of osteoinductivity Bone Morphogenetic Proteins (BMPs), the bone repair process has been greatly advanced by applying these proteins for therapeutic use. Some of the BMPs, such as BMP-2, in particular have been well studied and have gained interest as therapeutic agents. BMP-2 induces bone formation in vivo by stimulating differentiation of mesenchymal stem cells toward an osteoblastic lineage, thereby increasing the number of differentiated osteoblasts capable of forming bone. The stimulation of BMP on osteoblast differentiation plays a major role in bone healing. Recently, regulatory agencies in the U.S., Europe, Canada and Australia have approved devices containing BMP-2 and BMP-7 as bone-graft substitutes for the treatment of long bone fractures and interbody fusions of the spine. Despite its strong osteoinductive activity, clinical use of BMP-2 has been hampered by the lack of suitable delivery systems. An efficacious delivery system is needed to have sustained BMP release with appropriate dosing at the defect site. Both in vitro and in vivo studies have suggested that a dose response can be produced to affect the cell activities and the bone formation rate. The longer the release time of the BMP-2, the more fully the cells expressed sustained osteoblastic traits in vitro and the more bone formation in vivo. Thus, there is a pressing need to develop a synthetic carrier that has high initial structural integrity and sustained release of single or multiple agents known to induce bone regeneration. At the same time, these materials should undergo slow controlled resorption, eliminating the need for subsequent surgical removal. Such materials could have great clinical value when incorporated into medical devices.
Metallic materials have been widely used due to their high mechanical strength. However, the high strength of metallic implants normally reduces the stress in the surrounding materials (stress shielding), which weakens the adjacent bones. In addition, metal implants may release ions, which can cause adverse tissue reactions.
Furthermore, bone fixation devices composed of metal have a number of known problems such as stress shielding at the implant site and possible removal in a second surgery. Thus, absorbable implants for bone fixation have been developed to provide strength for healing and biodegradation for eventual replacement of the device with bone tissue. Design of bone fixation devices must consider tensile and bending strengths, their respective elastic modulus, biocompatibility, ability to support new bone growth, 3-dimensional structure and density, porosity and rate of degradation. Natural bone has a bending modulus in the range of about 3 to 30 MPa. An optimum bone fixation device is expected to be near or in this range for desired clinical utility. Although this has been generally recognized as a factor it has not been successfully put into practice.
Current devices are made from absorbable polymers and/or minerals, and often in a composite form. The minerals are most often calcium phosphate compounds. The absorbable polymers are most often synthetic aliphatic polyesters, polyethers, polycarbonates or their combinations. A problem with absorbable polymers is that in non-fiber form their strength is low. Absorbable fibers have much improved tensile strength, but suffer from low bending modulus. A problem with calcium phosphates is that despite high hardness, they are brittle. Thus, the right combination of these components is lacking in the current absorbable bone fixation devices.
In contrast to metallic implants, polymer-based implants have a more stable bone/implant interface during physiological loading. In addition, some polymers are biodegradable in vivo, and can be gradually replaced by living tissue, which is the best repair for defects. Unfortunately, polymers have relatively poor mechanical properties, which greatly restrict their usefulness in many applications. A second drawback arises because nearly all polymeric materials are bioinert, so they are consequently not osteoconductive, resulting in poor surface continuity. In order to achieve the osteoconductivity of the polymeric material, calcium phosphate, a bioactive ceramic material, is added to the polymer matrix to produce calcium phosphate-reinforced polymer composites. Most of these composites still have the low mechanical strength as pure polymer materials. Thus, there is a pressing need to identify novel calcium phosphate-reinforced polymer composites with sufficient mechanical strength for load-bearing skeletal implants.
Calcium phosphate (CaP)-reinforced polymer composites were originally envisioned as biomaterials for bone replacement on the basis of producing appropriate mechanical compatibility, as well as the required biocompatibility. According to published reports, up to 50 wt % of CaP was incorporated into the polymer matrix to achieve sufficiently high values of elastic modulus. Unfortunately, the composites lacked sufficient toughness for use in different applications.
There are a number of factors that influence the design of a skeletal implant. Structurally, bone is a nano carbonated hydroxyapatite (calcium phosphate) reinforced fibrous collagen composite. The calcium phosphate crystals, which take the form of platelets, are embedded within the collagen fiber matrix and are aligned along the fibers. These mineral-containing fibrils are arranged into lamellar sheets, which run helically with respect to the major axis of the cylindrical osteons. The preferential orientation of bone minerals and the interfacial bonding between the mineral and collagen fibers play an important role in determining the overall mechanical performance of the bone. Thus, the stiffness or average elastic modulus of bone is variable, but lies in the range of 3 to 30 GPa. At least three basic features must be addressed in device design: the property match between bone and the material of construction, the interface between this material and the bone, and the long-term stability of the overall assembly in the in-vivo environment.
Natural bone development and regeneration are regulated by a series of growth factors, so it is often desirable to deliver more than one of multiple exogenous growth factors during bone formation and repair. It has been found that a combination of BMP-2 and transforming growth factor-β (TGF-β) greatly enhanced bone healing compared to BMP-2 or TGF-β delivered separately. Unfortunately, most drug delivery systems are not able to systematically control the delivery multiple growth factors. It would be advantageous if sequential delivery can be designed into a carrier system. To achieve a maximum benefit, it is best to mimic nature's delivery of multiple growth factors in a programmed, sequential manner. Thus, the type and delivery kinetics of growth factors, and the type of carrier material all play a decisive role in the therapeutic success of any bone-repair process.
Therefore, a novel CaP-reinforced biodegradable polymer continuous-yarn composite is needed that features a biomimetic coating on the yarns to gain a high modulus. Furthermore, a new calcium fibrous polymer composite with a Young's modulus matched to natural bone, sufficient mechanical strength to support reasonable loads during the healing process, excellent biocompatibility, capability of controlled release of drugs, good osteoconductivity and osteoinductivity to enhance both bone formation and ingrowth, appropriate degradation rate, and capability of being replaced by natural bone in the long-term, is needed. Furthermore, it is desirable to provide a calcium mineral coated biodegradable yarn composite.